The present invention relates to a process for coating solid pharmaceutical preparations using an aqueous coating material including an enteric polymer and a specific class of plasticizer for the polymer. The invention also relates to the coated preparations thus obtained.
There are many reasons why solid pharmaceutical preparations need to be coated with an essentially continuous film. One such reason may be that the pharmaceutical is intended to pass through the stomach unaffected, only to be released in the intestines--in such a case, the pharmaceutical would be coated with a "enteric" coating which is impermeable to gastric juices, thus protecting the pharmaceutical from dissolution in the stomach. Other reasons for coating pharmaceutical preparations may be the need to protect the preparation from the effect of atmospheric oxygen or moisture. Nowadays, high polymers are most commonly used to produce the coating film.
Normally, however, the film-forming polymer is incapable of forming a suitably continuous film by itself and it is necessary to incorporate a plasticizer into the coating composition. Although, the nature of such plasticizers is restricted by the requirement that they should be safe to administer to human beings, a very wide range of compounds has been proposed for use as the plasticizer in such coating compositions and many of the compounds proposed are used in actual practice. For example, PCT publication No. 80/00659 suggests the use of propylene glycol, glycerol, glyceryl triacetate, polyethylene glycol, triethyl citrate, tributyl citrate, diethyl phthalate and dibutyl phthalate. Glycerides of higher fatty acids (particularly stearic acid) are proposed for use as plasticizers in "Coating of Pharmaceuticals", in the Modern Pharmaceutical Preparation Technology Series No. 1, published by Nihon Kogyo-gijutsu Renmei (The Industrial Technology League of Japan), 1969, and in Remington's Pharmaceutical Science, 14th Edition, Mack Publishing Co., 1970. One of the plasticizers illustrated in Japanese Patent Application Kokai (i.e. as laid open to public inspection) No. 104823/81 is described as "monoglyceride", but it is clear from the context of that specification and from the prior art that the "monoglyceride" referred to is a glyceride of a higher fatty acid.
Normally, the coating composition will be applied to the solid preparation as a solution or suspension in an appropriate liquid medium which, after application, is then removed, leaving the desired polymer film. Of course, the nature of the liquid medium chosen may constrain the choice of plasticizer or, conversely, the plasticizer chosen may place constraints upon the choice of medium. In general, the coating composition may be applied in any one of the following four systems:
(1) A system in which both the high polymer and the plasticizer are soluble in the liquid coating vehicle; PA0 (2) a system in which the high polymer is soluble in the coating vehicle but in which the plasticizer is insoluble; PA0 (3) a system in which the high polymer is insoluble in the coating vehicle, but the plasticizer is soluble; and PA0 (4) a system in which both the high polymer and the plasticizer are insoluble in the coating vehicle.
In systems (1)-(3), the coating vehicle has the effect of enhancing phase solubility between the plasticizer and the film-forming high polymer and, in this case, even plasticizers having relatively low plasticizing ability will provide the film with adequate plasticity. On the other hand, where both the high polymer and the plasticizer are insoluble in the coating vehicle, as in system (4), it is necessary to employ a higher grade of plasticizer, in order to ensure that the film has adequate plasticity. Thus, although plasticizers useful in system (4) are generally equally useful in systems (1)-(3), plasticizers useful in systems (1)-(3) are not necessarily useful as plasticizers in system (4).
Most compounds known for use as organic solvents are easily capable of dissolving such organic materials as high polymers and plasticizers, and a wide variety of compounds are known for use as organic solvents. Accordingly, when the coating vehicle is an organic solvent it rarely forms a system of type (4). Systems of type (4) usually contain water as the coating vehicle, although, for a number of reasons, such water-based systems have been relatively rare in practice. However, in recent years, various considerations, such as safety, economics and the avoidance of pollution, have made systems based upon organic solvents relatively less desirable than aqueous systems and systems of type (4) using water as the coating vehicle are beginning to be of practical importance.
Particularly important from the industrial point of view are enteric coating agents using water as the coating vehicle. High polymers employed for enteric coatings should be essentially insoluble in water in order to fulfill their function. Moreover, the plasticizer employed should be essentially insoluble in water. If the plasticizer is very soluble in water, the film produced with such a plasticizer becomes permeable to gastric juices, so that an enteric coating is not achieved and the pharmaceutical may be released in the stomach or inactivated or decomposed by permeated gastric juices. It is, therefore, necessary that the plasticizer employed should be essentially insoluble in water, at least, to the extent that it does not completely dissolve in water.
On the other hand, we have surprisingly found that the plasticizer should not be completely insoluble in water when used in a system of type (4), since a completely insoluble plasticizer will not allow a continuous film to be produced.
A further constraint upon the choice of plasticizer is that, as explained above, for an enteric coating using water as the coating vehicle in a system of type (4), a relatively high quality plasticizer is needed and such plasticizers are highly desired by the pharmaceutical industry.
We have now found that the mono- and di-glycerides of saturated aliphatic carboxylic acids having from 6 to 10 carbon atoms ("intermediate fatty acids"), but surprisingly not the corresponding triglycerides, meet the requirements outlined above and that they are especially valuable in that they can be used in systems of the type (4).